The Aims will identify genetic variation that influences risk of postpartum breast cancer (PPBC) and for which estimates of these effects can be used to inform screening protocols on an individualized basis. The Aims are:
Aim 1: Identify single nucleotide polymorphisms (SNPs) associated with incidence of postpartum breast cancer across the whole genome. While individual genes like Insulin-like Growth Factor Binding Protein 5 (IGFBP5) and Pregnancy-Associated Plasma Protein A (PAPP-A) have been proposed as drivers of PPBC, the genome-wide significance of alternate alleles in these genes nor allelic variation elsewhere in the genome have been tested. I will use a traditional logistic regression model to do a genome-wide association study (GWAS), comparing PPBC cases to non-PPBC controls using data from the UK Biobank. This GWAS will identify high-impact variants and may elucidate genetic mechanisms of PPBC.
Aim 2: Implement polygenic genotype-by-environment models to describe overall genetic risk of postpartum breast cancer. I hypothesize that, like in most disease states, there are many SNPs that have small effects on risk of PPBC. To test this hypothesis, I will (i) estimate the heritability of PPBC using maximum likelihood estimation and (ii) define a polygenic risk score (PRS) for PPBC using data from the UK Biobank. The heritability estimates will provide clarity on the true impact of genetics on PPBC incidence and outcomes, and the PRS can be used in the clinical setting to inform screening protocols and potential prophylactic treatments.
Impact: Upon completion of these studies, I will have significantly increased our knowledge of the genetic basis of PPBC risk. I will have identified key variants with high significance as well as a profile of variants that together provide a single estimate of genetic risk.
